Three-Component Synthesis of a Library of m-Terphenyl Derivatives with Embedded β-Aminoester Moieties

Article abstract of DOI:10.1021/acscombsci.8b00137

The three-component reaction between alkyl- or arylamines, β-ketoesters and chalcones in refluxing ethanol containing a catalytic amount of Ce(IV) ammonium nitrate allowed the construction of a large library of highly substituted dihydro-m-terphenyl derivatives containing β-alkylamino- or β-arylamino ester moieties. This process generates three new bonds and one ring and proceeds in high atom economy, having two molecules of water as the only side product. Another domino process, in which the original MCR was telescoped with a subsequent aza Michael/retro-aza Michael sequence, allowed the one-pot preparation of a library of compounds with a N-unsubstituted β-aminoester fragment. Finally, to extend the structural diversity of these libraries, we also examined the aromatization of the central ring of our compounds in the presence of dichlorodicyanoquinone. This reaction sequence did not affect the integrity of a stereogenic center belonging to the amino component.

Full text of DOI:10.1021/acscombsci.8b00137

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Article
Three-component synthesis of a library of m-terphenyl
derivatives with embedded #-aminoester moieties
Damiano Rocchi, Juan Francisco González, Jorge Gómez-Carpintero, Víctor
González-Ruiz, M. Antonia Martín, Vellaisamy Sridharan, and J. Carlos Menéndez
ACS Comb. Sci., Just Accepted Manuscript • DOI: 10.1021/acscombsci.8b00137 • Publication Date (Web): 24 Sep 2018
Downloaded from http://pubs.acs.org on September 25, 2018
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Threeꢀcomponent synthesis of a library of mꢀ
terphenyl derivatives with embedded βꢀaminoester
moieties
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a
Damiano Rocchi,a Juan F. González,a Jorge Gómez-Carpintero, Víctor González-Ruiz,b,† M.
Antonia Martín,b Vellaisamy Sridharan,c,d J. Carlos Menéndeza,*
a
Unidad de Química Orgánica y Farmacéutica, Departamento de Química en Ciencias
Farmacéuticas, Facultad de Farmacia, Universidad Complutense, 28040 Madrid, Spain.
b Unidad de Química Analítica, Departamento de Química en Ciencias Farmacéuticas, Facultad
de Farmacia, Universidad Complutense, 28040 Madrid, Spain.
c Organic Synthesis Group, Department of Chemistry, School of Chemical and Biotechnology,
SASTRA University, Thanjavur 613401, Tamil Nadu, India.
d
Department of Chemistry and Chemical Sciences, Central University of Jammu, Rahyaꢀ
Suchani (Bagla), DistrictꢀSamba, Jammuꢀ181143, Jammu and Kashmir, India.
KEYWORDS. Terphenyl derivatives; carbocycle construction; multicomponent reactions;
chalcones.
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ABSTRACT. The threeꢀcomponent reaction between alkylꢀ or arylamines, βꢀketoesters and
chalcones in refluxing ethanol containing a catalytic amount of Ce(IV) ammonium nitrate
allowed the construction of a large library of highly substituted dihydroꢀmꢀterphenyl derivatives
containing βꢀalkylaminoꢀ or βꢀarylamino ester moieties. This process generates three new bonds
and one ring and proceeds in high atom economy, having two molecules of water as the only side
product. Another domino process, in which the original MCR was telescoped with a subsequent
aza Michael/retroꢀaza Michael sequence, allowed the oneꢀpot preparation of a library of
compounds with a Nꢀunsubstituted βꢀaminoester fragment. Finally, in order to extend the
structural diversity of these libraries, we also examined the aromatization of the central ring of
our compounds in the presence of DDQ. This reaction sequence did not affect the integrity of a
stereogenic center belonging to the amino component.
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INTRODUCTION
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Teraryl moieties are important structural motifs that are inherent to many natural products and
synthetic molecules that have been widely used as building blocks in medicinal chemistry1 and
materials science. In particular, mꢀterphenyl (MTPs, Figure 1) constitutes the structural core of
several terphenyl natural products2 such as trifucol,3 dictyoterphenyl4 and the regioisomeric
neosesquilignans macranthol,5 dunnianol6 and simonsinol.7 Among these compounds,
macranthol has shown interesting biological properties such as the ability to promote
hippocampal neuronal proliferation.8 Synthetic mꢀterphenyl derivatives have also exhibited
various pharmacologically interesting properties such as antiprotozoal activity,9 cyclooxygenase
2 inhibition10 and antiarthritic activity.11 Furthermore, MTPs have also attracted much attention
because of their high thermal stability and unusual electronic properties due to their broken
conjugation, making them particulary important in materials science. Some applications in this
area include the construction of artificial helical and doubly helical polymers,12 dyeꢀsensitized
solar cells,13 organic light emission diodes (OLEDs),14 liquid crystals for optoelectronic
applications15 and cation sensors.16 Finally, terphenyl frameworks are the basis of several types
of structures of relevance in supramolecular chemistry11,14,17 and have been used as efficient
ligands for metalꢀcatalyzed synthetic reactions.18
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O
HO
OH
HO
OH
OH
OH
H2N
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HO
OH
OMe
OH
HO
OH
Trifucol
Dictyoterphenyl A
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CH2
CH2
R3
R2
OH
R4
R1
CH2
Dunnianol R1 = R3 = H, R2 = R4 = OH
Macranthol R1 = R4 = OH, R2 = R3 = H
Simonsinol R1 = R4 = H, R2 = R3 = OH
Figure 1. Structures of representative MTPꢀderived natural compounds
The importance of terphenyl frameworks has stimulated the development of a fair amount of
synthetic methodology in this area.19 For the case of mꢀterphenyls, the most commonly employed
strategies (Scheme 1) can be summarized as follows: (a) arylꢀaryl bond formation involving
transitionꢀmetalꢀcatalyzed reactions;19 (b) reaction of 1,2,3ꢀtrihalobenzenes20 or 2ꢀlithioꢀ1,3ꢀ
dihalobenzenes21 with an aryl Grignard reagent via aryne intermediates; (c) generation of the
central benzene ring by cycloaddition reactions22 or Michaelꢀcyclocondensation sequences;23 (d)
pseudomulticomponent reactions between 2ꢀbromoacrylates and phenylacetylenes via a
Sonogashiraꢀcycloaddition mechanism.24
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X
Cross-coupling
Br
X
Cl
R
R
R
MgBr
R
X
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[4+2] Cycloaddition
R3
R1
R3
R1
R2
R2
Michael/cyclocondensation
R1
R2
R1
R2
O
O
O
S
S
O
Tol
O
Tol
Pseudo-MCRs
CO2R2
Br
R1
R1
R1
CO2R2
CO2R2
Scheme 1. Representative disconnections of the mꢀterphenyl framework
All the methods summarized above furnish fully aromatic terphenyl derivatives. However, the
removal of aromaticity from bioactive compounds is a wellꢀestablished methodology for
improving aqueous solubility, a key objective in drug discovery and development.25 Therefore,
methodology leading directly to such systems is important in drug discovery programs. In
particular, the development of multicomponent reactions leading to pharmacologically relevant
frameworks having partially saturated rings is of great importance in view of the high synthetic
efficiency associated to these reactions and their potential in the construction of diversityꢀ
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oriented libraries.26 In this context, we have described in preliminary fashion a diastereoselective
threeꢀcomponent reaction that affords 1,3ꢀdiarylꢀ1,2,3,4ꢀtetrahydrobenzene derivatives from
alkylamines, βꢀketoesters, and chalcones in the presence of catalytic Ce(IV) ammonium nitrate
(CAN).27 Subsequently, we employed this reaction as the basis for oneꢀpot routes to heterocyclic
systems such as quinazolines28 and carbazoles,29 without isolation of the intermediate terphenyls.
Almost simultaneously with our initial communication, Shi reported another multicomponent
process from malononitrile, nitrostyrenes and arylmethylenemalononitriles leading to tetrahydroꢀ
mꢀterphenyls as diastereomer mixtures.30 Recently, Li described a reaction essentially identical
to ours that led to cyclohexaꢀ1,3ꢀdienꢀ2ꢀamines but that (with two exceptions) was restricted to
aromatic amines and required the use of stoichiometric amounts of the neurotoxic and highly
reactive AlCl3 as a promoter.31
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Due to the importance of the mꢀterphenyl framework, we now describe in full our work on the
optimization of the multicomponent synthesis of libraries of dihydroterphenyls from acyclic
precursors (Scheme 2). We also include our studies on their dehydrogenation in order to increase
the scope of library generation by this method.32 All these libraries have the further advantage
that the compounds contain a βꢀaminoester substructure, a very attractive moiety in drug
discovery projects because of its presence in a large number of pharmacologically relevant
structures with varied activities.33 Furthermore, methods for obtaining cyclic βꢀaminoacid or βꢀ
aminoesters are scarce in the literature34 in spite of their considerable importance in medicinal
chemistry, both for themselves and as components of βꢀpeptides and peptidomimetics resistant to
proteolysis.
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Scheme 2. Multicomponent disconnection of 5,6ꢀdihydroterphenyls examined in this article
RESULTS AND DISCUSSION
The structural diversity of the starting materials (chalcones 1, βꢀdicarbonyl compunds 2 and
amines 3) employed for the construction of our library is summarized in Figure 2. The starting
chalcones 1 were either commercially available or prepared from aromatic ketones and aromatic
aldehydes according to literature procedures.35 All dicarbonyl compounds 2 and amines 3 were
of commercial origin.
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Figure 2. Structural diversity of chalcones 1, βꢀdicarbonyl compounds 2 and primary amines 3
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Although our preliminary study had revealed conditions for the synthesis of 1ꢀhydroxyꢀ1,2,3,6ꢀ
tetrahydroꢀmꢀterphenyl derivatives via a multicomponent reaction, the relatively low stability of
these compounds made its application to the library construction somewhat impractical. This
prompted us to seek the in situ dehydration of these intermediates to furnish dihydroterphenyls.
Our optimization study was performed for the model reaction leading to compound 4{1,1,1}
from ethyl acetoacetate, butylamine and the unsubstituted chalcone. It involved initially the use
of a variety of Lewis acids (ytterbium triflate, yttrium triflate, indium trichloride, CAN) at 10
mol% concentration in refluxing ethanol, with the best results being obtained for the latter
catalyst (entries 1ꢀ4). Lowering the catalyst load to 5 mol% did not cause an appreciable change
(entry 5), but a drop in yield was observed upon a further reduction of catalyst to 2.5% (entry 6).
Some alternative solvents were also examined with no improvement over ethanol (methanol,
entry 7; acetonitrile, entry 8). The use of focused microwave irradiation in EtOH in the presence
of 5% CAN allowed a dramatic decrease in reaction time (1 vs 14 h), although the yield was
slightly lower (entry 9). Finally, a control experiment showed that the reaction gave only a small
amount of the product in the absence of catalyst.
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Table 1. Optimization studies for the synthesis of compound 4{1,1,1}.
Entry
Catalyst
Conditionsa
Solvent
EtOH
Yield, %
1
2
Yb(OTf)3, 10%
Y(OTf)3, 10%
A
A
58
15
EtOH
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InCl3, 10%
CAN, 10%
CAN, 5%
A
A
EtOH
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89
EtOH
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5
A
A
A
A
B
A
EtOH
EtOH
MeOH
CH3CN
EtOH
EtOH
88
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CAN, 2.5%
CAN, 5%
CAN, 5%
CAN, 5%
None
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80
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75
10
Traces
aReaction conditions: A. Reflux temperature of the chosen solvent, 14 h. Focused microwave,
b
140 °C, 1 h
With these results in hand, we proceeded to build the compound library (Scheme 3 and Table 2).
We used in most cases the microwaveꢀassisted conditions due to the shorter reaction times, in
spite of the slightly lower yields. For scaling up the reactions, the reflux conditions were
preferable. A comparison between both conditions has been carried out in some cases and the
results can be found in Table 2 (entries 10, 11, 16, 20, 23 and 25).
The microwaveꢀpromoted reaction was normally carried out at 140 °C for 2.5 h, except in those
cases where the Ar1 or Ar2 groups bear an oꢀnitro substituent; these reactions required only 100
°C for the same time, probably due to an enhanced electrophilicity of the chalcone (see Table 2
below, entries 10, 16, 19, 22, 23, 24).
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O
4
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CAN (5%)
EtOH, reflux
or EtOH, MW
(140 °C, 2.5 h)
Ar1
Ar2
R1NH2
1
Ar1
Ar2
3
CO2R2
NHR1
8
O
O
9
H3C
OR2
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4
2
Scheme 3. Threeꢀcomponent synthesis of dihydroꢀmꢀterphenyl derivatives with an embedded βꢀ
aminoester moiety
The results obtained in the reaction with alkylamines are summarized in Table 2, and prove the
possibility to introduce structural variations either at the alkylamino group (R1 substituent) and at
the ester functional group (R2 substituent), including the preparation of thioesters (entry 2).
Regarding the terphenyl framework itself, our results show that the reaction tolerates well the
presence of unsubstituted phenyl groups and phenyls bearing either electronꢀreleasing or
electronꢀwithdrawing groups both at Ar1 (unsubstituted phenyl: entries 1ꢀ5, and 7ꢀ13; phenyl
with electronꢀreleasing groups: entries 6, and 14ꢀ16; phenyl with electronꢀwithdrawing groups:
entries 17ꢀ24 and 30) and at Ar2 (unsubstituted phenyl: entries 1ꢀ6, 14, 20, 22, 25, 27 and 29;
phenyl with electronꢀreleasing groups: entry 15; phenyl with electronꢀwithdrawing groups:
entries 7ꢀ11, 16ꢀ19, 21, 23, 24 and 30). The method was rather insensitive to steric hindrance in
either of the aromatic rings, as shown by the preparation of several examples of compounds 4
bearing bulky substituents at their oꢀ positions (entries 22ꢀ24 for Ar1 and 10, 11, 16, 19, 24, 30
for Ar2). Furthermore, we also examined the introduction of several heteroaromatic substituents
at Ar1 (entries 25ꢀ28), Ar2 (entries 12, 13, 26 and 28) or both (entries 26 and 28), and we also
carried out a reaction with a vinylogous chalcone, which furnished the styryl derivative
4{21,1,1} (entry 29).
Table 2. Results obtained in the threeꢀcomponent reaction starting from alkylamines
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Method Aa
Method Bb
Entry Compound R1
R2
Ar1
Ar2
Yield, % t, h Yield, % Temp,°C
6
7
8
9
1
2
4{1,1,1}
4{1,4,1}
nꢀBu
nꢀBu
OEt
Ph
Ph
Ph
Ph
88
75
8
8
75
ꢀꢀ
140
ꢀꢀ
StꢀBu
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3
4
4{1,1,2}
4{1,3,2}
PhCH2
PhCH2
OEt
Ph
Ph
Ph
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80
8
8
ꢀꢀ
ꢀꢀ
ꢀꢀ
ꢀꢀ
OtꢀBu Ph
5
6
4{1,1,3}
Ph(CH2)2 OEt
Ph
Ph
79
ꢀꢀ
8
ꢀꢀ
ꢀꢀ
4{13,1,1} nꢀBu
OEt
OEt
OEt
OEt
OEt
4ꢀMeC6H4
Ph
ꢀꢀ
ꢀꢀ
ꢀꢀ
ꢀꢀ
8
65
67
80
72
74
140
140
140
140
100
7
4{2,1,1}
4{3,1,1}
4{4,1,1}
4{5,1,1}
nꢀBu
nꢀBu
nꢀBu
nꢀBu
Ph
Ph
Ph
Ph
4ꢀClC6H4
4ꢀBrC6H4
4ꢀO2NC6H4
2ꢀO2NC6H4
ꢀꢀ
8
ꢀꢀ
9
ꢀꢀ
10
78
11
4{6,1,1}
nꢀBu
OEt
Ph
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ꢀꢀ
8
65
140
12
13
4{8,1,1}
4{9,1,1}
nꢀBu
nꢀBu
OEt
OEt
Ph
Ph
ꢀꢀ
ꢀꢀ
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67
140
140
ꢀꢀ
ꢀꢀ
14
15
16
17
18
19
20
21
22
23
4{31,1,1} nꢀBu
4{11,1,1} nꢀBu
4{14,1,1} nꢀBu
4{15,1,1} nꢀBu
4{16,1,1} nꢀBu
4{17,1,1} nꢀBu
4{18,1,1} nꢀBu
4{19,1,1} nꢀBu
4{22,1,1} nꢀBu
4{23,1,1} nꢀBu
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
4ꢀMeOC6H4
4ꢀMeOC6H4
4ꢀMeC6H4
4ꢀClC6H4
Ph
ꢀꢀ
ꢀꢀ
8
73
72
67
75
78
79
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84
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140
140
100
140
140
100
140
140
100
100
4ꢀMeOC6H4 ꢀꢀ
2ꢀO2NC6H4
4ꢀClC6H4
4ꢀBrC6H4
2ꢀO2NC6H4
Ph
75
ꢀꢀ
ꢀꢀ
ꢀꢀ
ꢀꢀ
8
4ꢀClC6H4
ꢀꢀ
4ꢀClC6H4
ꢀꢀ
4ꢀBrC6H4
4ꢀBrC6H4
2ꢀO2NC6H4
2ꢀO2NC6H4
86
ꢀꢀ
4ꢀBrC6H4
Ph
ꢀꢀ
ꢀꢀ
8
ꢀꢀ
4ꢀBrC6H4
82
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24
25
4{24,1,1} nꢀBu
4{25,1,1} nꢀBu
OEt
OEt
2ꢀO2NC6H4
2ꢀO2NC6H4
Ph
ꢀꢀ
ꢀꢀ
8
62
73
100
140
71
7
8
9
26
27
4{7,1,1}
nꢀBu
OEt
OEt
ꢀꢀ
ꢀꢀ
ꢀꢀ
ꢀꢀ
70
70
140
140
10
11
12
13
14
15
16
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4{12,1,1} nꢀBu
Ph
Ph
28
29
4{10,1,1} nꢀBu
4{21,1,1} nꢀBu
OEt
OEt
ꢀꢀ
ꢀꢀ
6
68
ꢀꢀ
140
ꢀꢀ
PhꢀCH=CH
4ꢀBrC6H4
70
30
4{20,1,1} nꢀBu
OEt
ꢀꢀ
ꢀꢀ
66
140
a Reflux in ethanol. Irradiation with focused microwaves (140 °C, 2.5 h, except entries 10, 16,
b
19, 22, 23 and 24: 100 °C, 2.5 h), in ethanol.
Regarding the role of Ce(IV) ammonium nitrate, radical intermediates could be in principle
expected due to its strong oxidant properties. However, our reaction proceeded with no
appreciable loss in yield when performed in the presence of 1,1ꢀdiphenylethylene, which is a
wellꢀknown radical trap. This evidence led us to conclude that in our system Ce(IV) acts simply
as a Lewis acid catalyst, as in many other cases described in the literature.36
At a second stage of our study, we investigated the use of aromatic amines as the third
component. As shown in Table 3, the reaction allowed the preparation of compounds bearing an
unsubstituted Nꢀphenyl substituent (R1 = Ph, entries 1, 9ꢀ11, 15ꢀ18, 20 and 21), as well as
compounds bearing electronꢀwithdrawing (entries 3ꢀ6, 8 and 14) or electronꢀreleasing (entries 2,
7, 12, 13, 19 and 22) groups at the nitrogen aromatic ring, with variations in the Ar1 and Ar2
aromatic rings similar to the ones described above. Compared with the previous case of
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alkylamines, the reactions were slower and required a higher catalyst load (25%). These
transformations were carried under reflux in all cases because the reaction times in microwaveꢀ
assisted conditions were too long to be of practical value.
10
11
12
13
14
15
16
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19
20
21
22
23
24
25
26
27
28
29
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 3. Results obtained in the threeꢀcomponent reaction starting from arylamines
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Method A
Entry
Compound
Ar1
Ar2
Ph
R1
Ph
R2
Et
Yield, % t, h
1
2
4{1,1,4}
4{1,1,5}
4{1,1,8}
4{1,1,9}
4{1,1,10}
4{1,1,11}
4{1,1,12}
4{1,1,13}
4{1,2,4}
4{4,1,4}
4{5,1,4}
4{5,1,5}
4{5,1,6}
4{5,1,8}
4{29,1,4}
4{14,1,4}
4{26,1,4}
4{24,1,4}
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
83
90
77
75
72
58
90
54
72
82
83
87
84
79
72
79
82
67
72
72
72
72
72
72
72
72
72
72
14
14
14
14
14
14
72
14
Ph
4ꢀMe2NC6H4 Et
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
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59
60
3
Ph
Ph
4ꢀFC6H4
4ꢀClC6H4
4ꢀBrC6H4
3ꢀClC6H4
Et
Et
Et
Et
4
5
Ph
6
Ph
7
Ph
3,5ꢀMe2C6H3 Et
8
Ph
3,5ꢀCl2C6H3
Et
Me
Et
9
Ph
Ph
Ph
Ph
10
11
12
13
14
15
16
17
18
4ꢀO2NC6H4
2ꢀO2NC6H4
2ꢀO2NC6H4
2ꢀO2NC6H4
2ꢀO2NC6H4
Et
4ꢀMe2NC6H4 Et
4ꢀMeOC6H4
Et
Et
Et
Et
Et
Et
4ꢀFC6H4
Ph
4ꢀMeOC6H4 2ꢀO2NC6H4
4ꢀMeC6H4
4ꢀO2NC6H4
2ꢀO2NC6H4
2ꢀO2NC6H4
2ꢀO2NC6H4
2ꢀO2NC6H4
Ph
Ph
Ph
19
20
21
22
4{27,1,6}
4{7,1,4}
2ꢀO2NC6H4
4ꢀMeOC6H4
Ph
Et
Et
Et
Et
82
81
85
86
14
72
72
14
Ph
4{12,1,4}
4{28,1,6}
Ph
2ꢀO2NC6H4
4ꢀMeOC6H4
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We next examined the preparation of Nꢀunsubstituted derivatives, which in principle would seem
to be feasible by using ammonia as the amine component. However, we have shown this reaction
to afford 4,6ꢀdiarylꢀ1,4ꢀdihydropyridines, which have been exploited for their neuroprotective
activity.37 This difference in behavior can be explained by the mechanistic proposal shown in
Scheme 4, where the βꢀenaminone generated initially from 2 and 3 adds to the chalcone to
furnish an imine that can tautomerize to two different enamines A and B. The first of them, more
stable, can cyclize to give a dihydropyridine only if R1 = H for steric reasons. For all other cases
R1 ≠ H), the only possibility is the cyclization of enamine B to yield compounds 4.
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Ar1
Ar1
R1 = H
ꢀ H2O
O
R1
HN
H3C
NH
Ar2
OR2
Ar2
OR2
Ar1
H3C
Ar1
O
O
O
CH3
O
Enamine A
O
Ar2
R1
1
H3C
R1
N
2 + 3
Ar2
OR2
H
OR2
N
Ar1
Ar1
Ar2
CO2R2
O
R1 ≠ H
ꢀ H2O
Imine
O
H2C
Ar2
NHꢀR1
R1
N
H
OR2
4
O
Enamine B
Scheme 4. Proposed explanation for the difference in product selectivity between primary
amines and ammonia
Due to the impossibility of employing ammonia as a starting material for our multicomponent
reaction, we resorted to an indirect method for the preparation of the Nꢀunsubstituted
compounds. Thus, we carried out the usual threeꢀcomponent reaction with butylamine and,
without isolation, treated in situ the initially formed product with ammonium formate as a source
of ammonia. Presumably, under these conditions an azaꢀMichael/retro azaꢀMichael process takes
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place that leads to the exchange of the butylamino and amino substituents (Scheme 5a). This
exchange is reversible, as shown by the fact that the reaction between the Nꢀunsubstituted
compound 4{1,1,14} and butylamine under our reaction conditions gives the Nꢀbutyl derivative
4{1,1,1} in 90% yield, as shown by a separate experiment. Therefore, the azaꢀMichael / retro
azaꢀMichael pathway is reversible, and the good results that we have obtained in the butylaminoꢀ
amino exchange must be ascribed to equilibrium displacement because of the large excess of
ammonium formate that we employ (Scheme 5b).
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Scheme 5. In situ butylaminoꢀamino exchange for the synthesis of Nꢀunsubstituted compounds 4
This domino process was applied to generate a library of Nꢀunsubstituted compounds 4{a,b,14}
in good to excellent yields, as summarized in Table 4. As in previous cases, the versatility of the
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method to yield compounds 4 with variously substituted phenyl rings at Ar1 and Ar2, as well as
5
6
heteroaryl substituents, was demonstrated.
7
8
9
Table 4. Results obtained in the synthesis of Nꢀunsubstituted compounds 4 by a threeꢀcomponent
reaction telescoped with an in situ butylaminoꢀamino exchange
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Entry Compound Ar1
Ar2
Yield, %
5
6
7
8
1
2
3
4
5
4{1,1,14} Ph
4{30,1,14} Ph
4{33,1,14} Ph
4{2,1,14} Ph
4{5,1,14} Ph
Ph
96
93
78
70
77
78
4ꢀMeOC6H4
4ꢀMeC6H4
4ꢀClC6H4
2ꢀO2NC6H4
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
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49
50
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52
53
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58
59
60
6
7
4{8,1,14} Ph
4{9,1,14} Ph
79
8
4{31,1,14} 4ꢀMeOC6H4 Ph
87
92
73
82
90
87
90
92
9
4{11,1,14} 4ꢀMeOC6H4 4ꢀMeOC6H4
10
11
12
13
14
15
4{13,1,14} 4ꢀMeC6H4
4{32,1,14} 4ꢀClC6H4
4{15,1,14} 4ꢀClC6H4
4{16,1,14} 4ꢀClC6H4
4{18,1,14} 4ꢀBrC6H4
4{19,1,14} 4ꢀBrC6H4
Ph
Ph
4ꢀClC6H4
4ꢀBrC6H4
Ph
4ꢀBrC6H4
16
17
18
19
4{25,1,14}
4{7,1,14}
4{12,1,14}
4{10,1,14}
Ph
Ph
74
77
76
78
Finally, in order to extend the structural diversity of our libraries, we examined the aromatization
of the central ring of mꢀterphenyl derivatives 4. Our initial attempts to perform this
dehydrogenation with PdꢀC at varying concentrations in several solvents at reflux conditions,
gave poor results. However, as shown in Scheme 6, this transformation was easily achieved by
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treatment with DDQ in toluene, at room temperature, and proceeded in excellent yields in all
cases studied, leading to a general method for the synthesis of fully aromatic compounds 5
(Table 5). For the case of the Nꢀunsubstituted derivatives 5{x,1,14}, it is interesting to note that
our method compares favorably with a recently described protocol involving an oxidative Nꢀ
debenzylation step and that requires the use of three equivalents of DDQ.33 In this context, it is
relevant to note that oxidizing compounds are a wellꢀknown source of toxic waste, and redox
economy has been identified as particularly relevant in terms of synthetic sustainability.38
10
11
12
13
14
15
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19
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21
22
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Scheme 6. Aromatization of compounds 4
Table 5. Results obtained in the synthesis of aromatic compounds 5 by dehydrogenation of 4
Entry
Compound
5{1,1,14}
5{13,1,14}
5{32,1,14}
5{15,1,14}
5{30,1,14}
5{19,1,14}
5{1,1,1}
Ar1
Ar2
R1
H
R2
Yield, %
99
1
2
3
4
5
6
7
8
Ph
Ph
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
4ꢀMeC6H4
4ꢀClC6H4
4ꢀClC6H4
Ph
Ph
H
96
Ph
H
95
4ꢀClC6H4
4ꢀMeOC6H4
4ꢀBrC6H4
Ph
H
97
H
97
4ꢀBrC6H4
Ph
H
96
nꢀBu
nꢀBu
93
5{32,1,1}
4ꢀClC6H4
Ph
92
9
5{10,1,1}
nꢀBu
OEt
95
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5{5,1,1}
Ph
2ꢀO2NC6H4
nꢀBu
OEt
OEt
91
88
5{24,1,1}
2ꢀNO2C6H4 2ꢀO2NC6H4
nꢀBu
6
7
8
9
12
13
5{20,1,1}
5{6,1,1}
4ꢀBrC6H4
nꢀBu
OEt
OEt
92
89
10
11
12
13
14
15
16
17
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Ph
nꢀBu
14
15
16
17
18
5{23,1,1}
5{19,1,1}
5{22,1,1}
5{14,1,1}
5{21,1,1}
2ꢀNO2C6H4 4ꢀBrC6H4
nꢀBu
nꢀBu
nꢀBu
nꢀBu
nꢀBu
OEt
OEt
OEt
OEt
OEt
94
92
82
90
93
4ꢀBrC6H4
4ꢀBrC6H4
2ꢀNO2C6H4 Ph
4ꢀMeC6H4
PhCH=CH
2ꢀO2NC6H4
Ph
Ph
Ph
19
20
5{1,1,2}
5{1,3,2}
Ph
Ph
PhCH2
PhCH2
Ph
OEt
78a
78
OtꢀBu
OEt
21
22
23
24
25
26
27
28
5{1,1,4}
5{1,1,12}
5{1,1,8}
5{1,1,11}
5{1,1,9}
5{1,1,10}
5{1,1,13}
5{4,1,4}
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
94
93
90
92
94
96
95
93
Ph
3,5ꢀMe2C6H3 OEt
Ph
4ꢀFC6H4
3ꢀClC6H4
4ꢀClC6H4
4ꢀBrC6H4
3,5ꢀCl2C6H3
Ph
OEt
OEt
OEt
OEt
OEt
OEt
Ph
Ph
Ph
Ph
4ꢀO2NC6H4
29
30
5{12,1,4}
5{7,1,4}
Ph
Ph
Ph
OEt
OEt
97
95
31
32
5{1,1,5}
Ph
Ph
Ph
Ph
4ꢀMe2NC6H4
H
OEt
94
96
5{1,3,14}
OtBu
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As a final check of the generality of our method, we studied the reaction starting from a chiral
substrate in order to investigate the possibility of racemization. As shown in Scheme 7, the
multicomponent reaction involving (E)ꢀ1,3ꢀdiphenylpropenone 1{1}, ethyl acetoacetate 2{1}
and (R)ꢀ1ꢀphenylethanꢀ1ꢀamine 3{15} afforded the corresponding dihydroterphenyl 4{1,1,15}.
This compound was isolated as a ca. 1:1 mixture of diastereomers, showing that the remote
stereocenter at the amine side chain had no influence on the stereochemical course of the
reaction. Compound 4{1,1,15}, without purification, was aromatized under our usual DDQ
conditions to give 5{1,1,15}, which proved refractary to analysis by chiral HPLC owing to its
very poor solubility in the usual reverseꢀphase mobile phases. To surmount this obstacle, we
hydrolyzed 5{1,1,15} under basic conditions and obtained the corresponding carboxylic acid 6,
which was more adequate for HPLC studies. Compound 6 was analyzed by HPLC with a column
containing ovoalbumin as chiral stationery phase, using as reference the corresponding racemic
material, which was obtained from racemic 3{15} using the same reaction sequence. In this
experiment, 6 was found to be enantiomerically pure within the detection limits of the HPLC
technique.
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Scheme 7. Absence of racemization in a sequence of reactions starting from a chiral amine
CONCLUSIONS
The threeꢀcomponent reaction between alkylꢀ or arylamines, βꢀketoesters, and chalcones in the
presence of a catalytic amount of Ce(IV) ammonium nitrate in refluxing ethanol allowed the
construction of a large library of dihydroꢀmꢀterphenyl derivatives functionalized with βꢀ
alkylaminoꢀ or βꢀarylamino ester moieties by creation of the central carbocyclic ring of the
terphenyl system via the generation of two new CꢀC bonds, plus an additional exocyclic CꢀN
bond corresponding to the amino side chain. Furthermore, the overall process proceeded in high
atom economy, since its only side product was water (two molecules per molecule of product).
The preparation of Nꢀunsubstituted derivatives was not possible by the original method, since the
reaction starting from ammonia, βꢀketoesters, and chalcones deviated towards the generation of
4,6ꢀdiarylꢀ1,4ꢀdihydropyridines. This problem was solved by designing a more complex oneꢀpot
domino process, in which the original MCR was telescoped in situ with a subsequent aza
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Michael / retro azaꢀMichael sequence. The aromatization of the central ring of the dihydroꢀmꢀ
terphenyl derivatives was readily achieved in the presence of DDQ at room temperature. This
reaction sequence did not alter the integrity of a stereogenic center at the nitrogen side chain.
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EXPERIMENTAL SECTION
General procedure for the preparation of chalcones 1 represented by the synthesis of 1{1}.
This compound was synthesized according to a reported procedure.39 A solution of acetophenone
(3.15 mL, 27 mmol) and benzaldehyde (2.7 mL, 27 mmol) in ethanol (120 mL) was added 1.1
mL of 6M aqueous sodium hydroxide solution. The reaction was stirred at room temperature and
monitored by TLC for completion. The precipitated solid was collected by filtration, washed
with water and hexane and purified by recrystallization from ethanol, affording chalcone {1}.
The desired product was obtained as white solid (3.9 g, 70% yield) and used for next step
without further purification.
General procedure for the preparation of N-alkyl substituted dihydro-m-terphenyls
4{a,b,1-3}, represented by the synthesis of 4{1,1,1}.
Method A
To a stirred solution of the ethyl acetoacetate (0.55 mL, 4.36 mmol) and butylamine (0.56 mL,
5.67 mmol) in ethanol (25 mL) was added CAN (120 mg, 0.21 mol). Stirring was continued for
30 min at room temperature. (E)ꢀ1,3ꢀDiphenylpropenone (1.0 g, 4.80 mmol), (1.1 eq) was then
added to the stirred solution and the mixture was heated under reflux for 8 hours. After
completion of the reaction, as indicated by TLC, the mixture was dissolved in ethyl acetate (50
mL), washed with water, brine, dried (anhydrous Na2SO4), and the solvent was evaporated under
reduced pressure. Final products were purified by flash silica column chromatography eluting
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yield).
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To a microwave tube containing a solution in EtOH (2 mL) of (E)ꢀ1,3ꢀdiphenylpropenone (1.0 g,
4.80 mmol) and CAN (120 mg, 0.21 mol) was added ethyl acetoacetate (0.55 mL, 4.36 mmol)
and butylamine (0.56 mL, 5.67 mmol). The tube was sealed, placed in the cavity of a CEM
Discover microwave oven and subjected to microwave irradiation at 140 ºC and 200 W. After a
period of 2ꢀ3 min, the temperature remained constant at 140 ºC. The reaction was performed at
100 ºC during 2.5 hours for the preparation of some compounds, namely 4{5,1,1}, 4{14,1,1},
4{17,1,1}, 4{22,1,1}, 4{23,1,1} and 4{24,1,1}. After completion of the reaction (2.5 hours), the
tube was cooled to room temperature and the solvent was removed in vacuum to dryness and
purified by column chromatography on silica gel eluting with petrol ether/EtOAc (9/1, v/v) and
obtained as yellow solid (1.23 g, 75% yield).
General procedure for the preparation of N-aryl substituted dihydro-m-terphenyls {a,b,4-
13} represented by the synthesis of 4{1,1,4}.
A solution of aniline (0.61 mL, 6.72 mmol), ethyl acetoacetate (0.79 mL, 6.24 mmol), (E)ꢀ1,3ꢀ
diphenylpropenone (1.0 g, 4.80 mmol) and CAN (263mg, 0.48 mmol) in EtOH (20 mL) was
refluxed for 72 h. After completion of the reaction, the reaction mixture was cooled, diluted with
ethyl acetate and washed with 1 M hydrochloric acid (2 x 5 mL), saturated sodium bicarbonate
solution (2 x 5 mL) and brine (5 mL). The organic phase was dried and the solvent was
evaporated under reduced pressure and the oily residue was purified by column chromatography
on silica gel, eluting with petroleum ether/EtOAc (8/2, v/v) and the target compound was
obtained as a yellow solid (1.6 g, 83% yield)
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General procedure for the preparation of N-unsubstituted dihydro-m-terphenyls {a,b,14}
represented by the synthesis of 4{1,1,14}.
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To a microwave tube containing a solution in EtOH (2 mL) of (E)ꢀ1,3ꢀdiphenylpropenone (417
mg, 2.00 mmol) and CAN (55 mg, 0.1 mmol) was added ethyl acetoacetate (0.23 mL, 1.82
mmol) and butylamine (0.23 mL, 2.37 mmol). The tube was sealed, placed in a CEM Discover
microwave oven and subjected to microwave irradiation, programmed at 150 ºC and 200 W.
After a period of 2ꢀ3 min, the temperature remained constant at 150 ºC. After 2.5 hours, the tube
was cooled to room temperature, ammonium formate (5 eq) was added to the mixture and the
reaction was continued under the same conditions for additional 60 minutes. The tube was
cooled to room temperature and the solvent was removed to dryness in vacuo. The residue was
purified by column chromatography on silica gel eluting with petrol ether/EtOAc (1/1, v/v) and
the target compound was obtained as a yellow solid (613 mg, 96% yield).
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General procedure for the aromatization of dihydro derivatives represented by the
synthesis of 5{1,1,1}.
To a stirred solution of ethylꢀ6ꢀbutylaminoꢀ2,4ꢀdiphenylꢀ2,3ꢀdihydro benzoate (563 mg, 1.5
mmol) in toluene (10 mL) was added DDQ (408 mg, 1.8 mmol) and the reaction mixture was
stirring at room temperature for 2 h. After extraction with ethyl ether (50 mL x 3), the combined
extracts were washed with H2O (50 mL), brine (50 mL), dried over anhydrous Na2SO4, filtered,
and concentrated in vacuo, to give a residue that was purified by flash chromatography on silica
gel with petroleum etherꢀethyl acetate mixture (9:1) and obtained as yellow solid (521 mg, 93%
yield).
Synthesis of (R)-5'-(1-phenylethylamino)-[1,1':3',1''-terphenyl]-4'-carboxylic acid (6). To a
stirred solution of ethyl 5'ꢀ((1ꢀphenylethyl)amino)ꢀ[1,1':3',1''ꢀterphenyl]ꢀ4'ꢀcarboxylate 5{1,1,15}
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(745 mg, 177 mmol) in EtOH (30 mL), was added 6M NaOH (20 mL) and the reaction mixture
was heated under reflux overnight. Afterwards, the mixture was cooled down to room
temperature and the NaOH was neutralized with HCl to pH 1. The aqueous phase was extracted
with dichloromethane (3 x 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated in
vacuo to yield the product as a pale brown solid (610 mg, 88%).
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HPLC study of compound 6. The enantiomeric purity of compound 6 was studied with an
ULTRON ESꢀOVM analytical column, 150 mm in length and 4.6 mm internal diameter and
particle size 5 µm. A 7:3 mixture of NaH2PO4 aqueous buffer (pH 5.7) and iPrOH was employed
as eluent. Flow rate was 1 ml/min and detection was performed by UV (358 nm), and each
experiment was run for 20 min. The retention times were of the 7.21 min 8.56 min for the S and
R enantiomers, respectively.
ASSOCIATED CONTENT
Supporting Information. The following file is available free of charge: Characterization data
and copies of spectra of compounds 4 ꢀ 6 (PDF).
AUTHOR INFORMATION
Corresponding Author
*J. Carlos Menéndez. Unidad de Química Orgánica y Farmacéutica, Departamento de Química
en Ciencias Farmacéuticas, Facultad de Farmacia, Universidad Complutense, 28040 Madrid,
Spain. Eꢀmail: josecm@ucm.es.
Present Addresses
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†
School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, 1211
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Geneva 4, Switzerland.
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Author Contributions
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The manuscript was written through contributions of all authors. All authors have given approval
to the final version of the manuscript.
Funding Sources
Ministerio de Economía y Competitividad (MINECO), grant CTQ2015ꢀ68380ꢀR.
ACKNOWLEDGMENT
Financial support from Ministerio de Economía y Competitividad (MINECO) through grant
CTQ2015ꢀ68380ꢀR is gratefully acknowledged.
ABBREVIATIONS
CAN, cerium(IV) ammonium nitrate; DDQ, dichlorodicyanoquinone.
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